Colon tumour cell death causes mTOR dependence by paracrine P2X4 stimulation.

Solid cancers exhibit a dynamic balance between cell death and proliferation ensuring continuous tumour maintenance and growth1,2. Increasing evidence links enhanced cancer cell apoptosis to paracrine activation of cells in the tumour microenvironment initiating tissue repair programs that support tumour growth3,4, yet the direct effects of dying cancer cells on neighbouring tumour epithelia and how this paracrine effect potentially contributes to therapy resistance are unclear. Here we demonstrate that chemotherapy-induced tumour cell death in patient-derived colorectal tumour organoids causes ATP release triggering P2X4 (also known as P2RX4) to mediate an mTOR-dependent pro-survival program in neighbouring cancer cells, which renders surviving tumour epithelia sensitive to mTOR inhibition. The induced mTOR addiction in persisting epithelial cells is due to elevated production of reactive oxygen species and subsequent increased DNA damage in response to the death of neighbouring cells. Accordingly, inhibition of the P2X4 receptor or direct mTOR blockade prevents induction of S6 phosphorylation and synergizes with chemotherapy to cause massive cell death induced by reactive oxygen species and marked tumour regression that is not seen when individually applied. Conversely, scavenging of reactive oxygen species prevents cancer cells from becoming reliant on mTOR activation. Collectively, our findings show that dying cancer cells establish a new dependency on anti-apoptotic programs in their surviving neighbours, thereby creating an opportunity for combination therapy in P2X4-expressing epithelial tumours.

Hippocampal neurodegeneration induces transient endogenous regeneration and long-term exhaustion of the neurogenic niche.

The hippocampal dentate gyrus, responds to diverse pathological stimuli through neurogenesis. This phenomenon, observed following brain injury or neurodegeneration, is postulated to contribute to neuronal repair and functional recovery, thereby presenting an avenue for endogenous neuronal restoration. This study investigated the extent of regenerative response in hippocampal neurogenesis by leveraging the well-established kainic acid-induced status epilepticus model in vivo. In our study, we observed the activation and proliferation of neuronal progenitors or neural stem cell (NSC) and their subsequent migration to the injury sites following the seizure. At the injury sites, new neurons (Tuj1+BrdU+ and NeuN+BrdU+) have been generated indicating regenerative and reparative roles of the progenitor cells. We further detected whether this transient neurogenic burst, which might be a response towards an attempt to repair the brain, is associated with persistent long-term exhaustion of the dentate progenitor cells and impairment of adult neurogenesis marked by downregulation of Ki67, HoPX, and Sox2 with BrdU+ cell in the later part of life. Our studies suggest that the adult brain has the constitutive endogenous regenerative potential for brain repair to restore the damaged neurons, meanwhile, in the long term, it accelerates the depletion of the finite NSC pool in the hippocampal neurogenic niche by changing its proliferative and neurogenic capacity. A thorough understanding of the impact of modulating adult neurogenesis will eventually be required to design novel therapeutics to stimulate or assist brain repair while simultaneously preventing the adverse effects of early robust neurogenesis on the proliferative potential of endogenous neuronal progenitors.

MK2 degradation as a sensor of signal intensity that controls stress-induced cell fate.

Cell survival in response to stress is determined by the coordination of various signaling pathways. The kinase p38α is activated by many stresses, but the intensity and duration of the signal depends on the stimuli. How different p38α-activation dynamics may impact cell life/death decisions is unclear. Here, we show that the p38α-signaling output in response to stress is modulated by the expression levels of the downstream kinase MK2. We demonstrate that p38α forms a complex with MK2 in nonstimulated mammalian cells. Upon pathway activation, p38α phosphorylates MK2, the complex dissociates, and MK2 is degraded. Interestingly, transient p38α activation allows MK2 reexpression, reassembly of the p38α-MK2 complex, and cell survival. In contrast, sustained p38α activation induced by severe stress interferes with p38α-MK2 interaction, resulting in irreversible MK2 loss and cell death. MK2 degradation is mediated by the E3 ubiquitin ligase MDM2, and we identify four lysine residues in MK2 that are directly ubiquitinated by MDM2. Expression of an MK2 mutant that cannot be ubiquitinated by MDM2 enhances the survival of stressed cells. Our results indicate that MK2 reexpression and binding to p38α is critical for cell viability in response to stress and illustrate how particular p38α-activation patterns induced by different signals shape the stress-induced cell fate.

Recent advances in bioengineered scaffold for in vitro meat production.

In vitro meat production via stem cell technology and tissue engineering provides hypothetically elevated resource efficiency which involves the differentiation of muscle cells from pluripotent stem cells. By applying the tissue engineering technique, muscle cells are cultivated and grown onto a scaffold, resulting in the development of muscle tissue. The studies related to in vitro meat production are advancing with a seamless pace, and scientists are trying to develop various approaches to mimic the natural meat. The formulation and fabrication of biodegradable and cost-effective edible scaffold is the key to the successful development of downstream culture and meat production. Non-mammalian biopolymers such as gelatin and alginate or plant-derived proteins namely soy protein and decellularized leaves have been suggested as potential scaffold materials for in vitro meat production. Thus, this article is aimed to furnish recent updates on bioengineered scaffolds, covering their formulation, fabrication, features, and the mode of utilization.

Ti2C-TiO2 MXene Nanocomposite-Based High-Efficiency Non-Enzymatic Glucose Sensing Platform for Diabetes Monitoring.

Diabetes is a major health challenge, and it is linked to a number of serious health issues, including cardiovascular disease (heart attack and stroke), diabetic nephropathy (kidney damage or failure), and birth defects. The detection of glucose has a direct and significant clinical importance in the management of diabetes. Herein, we demonstrate the application of in-situ synthesized Ti2C-TiO2 MXene nanocomposite for high throughput non-enzymatic electrochemical sensing of glucose. The nanocomposite was synthesized by controlled oxidation of Ti2C-MXene nanosheets using H2O2 at room temperature. The oxidation results in the opening up of Ti2C-MXene nanosheets and the formation of TiO2 nanocrystals on their surfaces as revealed in microscopic and spectroscopic analysis. Nanocomposite exhibited considerably high electrochemical response than parent Ti2C MXene, and hence utilized as a novel electrode material for enzyme-free sensitive and specific detection of glucose. Developed nanocomposite-based non-enzymatic glucose sensor (NEGS) displays a wide linearity range (0.1 µM-200 µM, R2 = 0.992), high sensitivity of 75.32 µA mM-1 cm-2, a low limit of detection (0.12 µM) and a rapid response time (~3s). NEGS has further shown a high level of repeatability and selectivity for glucose in serum spiked samples. The unveiled excellent sensing performance of NEGS is credited to synergistically improved electrochemical response of Ti2C MXene and TiO2 nanoparticles. All of these attributes highlight the potential of MXene nanocomposite as a next-generation NEGS for on the spot mass screening of diabetic patients.

Nanosheets Based Approach to Elevate the Proliferative and Differentiation Efficacy of Human Wharton's Jelly Mesenchymal Stem Cells.

Mesenchymal stem cell (MSC)-based therapy and tissue repair necessitate the use of an ideal clinical biomaterial capable of increasing cell proliferation and differentiation. Recently, MXenes 2D nanomaterials have shown remarkable potential for improving the functional properties of MSCs. In the present study, we elucidated the potential of Ti2CTx MXene as a biomaterial through its primary biological response to human Wharton's Jelly MSCs (hWJ-MSCs). A Ti2CTx nanosheet was synthesized and thoroughly characterized using various microscopic and spectroscopic tools. Our findings suggest that Ti2CTx MXene nanosheet exposure does not alter the morphology of the hWJ-MSCs; however, it causes a dose-dependent (10-200 µg/mL) increase in cell proliferation, and upon using it with conditional media, it also enhanced its tri-lineage differentiation potential, which is a novel finding of our study. A two-fold increase in cell viability was also noticed at the highest tested dose of the nanosheet. The treated hWJ-MSCs showed no sign of cellular stress or toxicity. Taken together, these findings suggest that the Ti2CTx MXene nanosheet is capable of augmenting the proliferation and differentiation potential of the cells.

Long noncoding RNAs in intestinal homeostasis, regeneration, and cancer.

Signaling pathways that regulate homeostasis and regeneration are found to be deregulated in various human malignancies. Accordingly, attempts have been made to target them at the protein level with little success. However, studies using high-throughput sequencing technologies suggest that only about 2% of the genome translates into proteins, whereas about 75% of the genome is transcribed into noncoding RNAs. Among noncoding RNAs, long noncoding RNAs (lncRNAs) have received tremendous attention in recent years as a crucial player in the regulation of almost all cellular processes involved in tissue homeostasis as well as in the development of various malignancies, including intestinal cancer. Emerging evidence suggests that lncRNAs play an instrumental role in the regulation of intestinal stem cells, injury-induced regeneration, and initiation and progression of intestinal tumors. Here, we summarize the recently discovered lncRNAs during intestinal homeostasis, regeneration, and tumorigenesis. We further present lncRNAs as diagnostic and therapeutic markers in intestinal pathologies.

Neuroinvasion of SARS-CoV-2 may play a role in the breakdown of the respiratory center of the brain.

The recent outbreak of the novel coronavirus, SARS-CoV-2, has emerged to be highly pathogenic in nature. Although lungs are considered as the primary infected organs by SARS-CoV-2, some of the other organs, including the brain, have also been found to be affected. Here, we have discussed how SARS-CoV-2 might infect the brain. The infection of the respiratory center in the brainstem could be hypothesized to be responsible for the respiratory failure in many COVID-19 patients. The virus might gain entry through the olfactory bulb and invade various parts of the brain, including the brainstem. Alternatively, the entry might also occur from peripheral circulation into the central nervous system by compromising the blood-brain barrier. Finally, yet another possible entry route could be its dispersal from the lungs into the vagus nerve via the pulmonary stretch receptors, eventually reaching the brainstem. Therefore, screening neurological symptoms in COVID-19 patients, especially toward the breakdown of the respiratory center in the brainstem, might help us better understand this disease.

Pediatric Ventriculoperitoneal Shunts and their Complications: An Analysis.

INTRODUCTION: Ventriculoperitoneal (VP) shunt is the most commonly utilized shunting procedure because of the capacity of the peritoneum to resorb fluid. Initial and subsequent peritoneal catheter placements can be done with relative ease. They are associated with a variety of complications. MATERIALS AND METHODS: The total number of patients operated in the study period was 96. We studied 41 operated patients of VP shunt who had various shunt-related complications and analyzed the predisposing risk factors and spectrum of complications. RESULTS: The mean age was 28 ± 32 months out of which 28 were males and 13 females. The etiology of hydrocephalus was aqueductal stenosis in 18, Arnold Chiari malformation in 10, Dandy-Walker malformation in 2, postmeningitis in 8 (pyogenic in 5 and tubercular in 3), postintraventricular hemorrhage in 2 patients and postencephalocele surgery in 1. CONCLUSION: With this retrospective review of complications of VP shunts, age at initial shunt insertion and the interval between the age of initial shunt placement and onset of complications were the most important patient-related predictors of shunt failure. The different predominant etiological factors responsible for early and late shunt failure were infective and mechanical complications, respectively.

Derivation and Characterization of Novel Cytocompatible Decellularized Tissue Scaffold for Myoblast Growth and Differentiation.

The selection of an appropriate scaffold is imperative for the successful development of alternative animal protein in the form of cultured meat or lab-grown meat. Decellularized tissues have been suggested as a potential scaffold for cultured meat production owing to their capacity to support an optimal environment and niche conducive to cell proliferation and growth. This approach facilitates the systematic development of 3D tissues in the laboratory. Decellularized scaffold biomaterials have characteristics of high biocompatibility, biodegradation, and various bioactivities, which could potentially address the limitations associated with synthetic bio-scaffold materials. The present study involved the derivation and characterization of a decellularized scaffold from mushroom tissue following subsequent assessment of the scaffold's capacity to support myogenic differentiation. Mushroom sections were soaked in nuclease and detergent solution for 4 days. Furthermore, decellularization was confirmed by histology and DAPI staining, which showed the removal of cellular components and nuclei. Myoblast cells were seeded onto decellularized tissue, which exhibited excellent cytocompatibility and promoted myogenic growth and differentiation. The study's findings can serve as a foreground for the generation of an edible and natural scaffold for producing a safe and disease-free source of alternative animal protein, potentially reducing the burden on the health sector caused by conventional animal protein production and consumption.